Obesity is a major worldwide health problem and highly prevalent among our veteran population. Therapeutic options are limited. Lifestyle change is effective but difficult to implement and available drugs are minimally effective and/or unsafe. Surgical therapy can be effective, but requires a major operation and is associated with several long-term complications. In spite of the problems with drug therapy to date, we believe there is an intriguing approach that needs further evaluation. That approach is to target mitochondria with agents that induce mild respiratory uncoupling. As discussed in the body of this application, mitochondrial uncoupling has the potential to divert caloric intake to heat production rather to energy storage as fat mass. Although vigorous uncoupling is likely dangerous, mild uncoupling (over time) could lead to safe weight loss in a manner that has been likened to exercise. Coenzyme Q (CoQ) has been advocated as an antioxidant and metabolically active compound offering health benefits. However, CoQ does not, or very poorly, penetrates mitochondrial membranes and has not proven effective. Therefore, attempts have been made to target CoQ to mitochondria. A common approach is to shorten the CoQ side chain and add a covalent attachment consisting of the positively charged cation, triphenylphosphonium (TPP). This has led to compounds we refer to as mitochondrial-targeted CoQ analogs (MTQAs). The prototype is the compound, mitoquinone (MitoQ), which has been developed as a mitochondrial-targeted antioxidant and is now under investigation for the treatment of neurodegenerative diseases, aging, hepatic steatosis, and other disorders. In recent VA supported work, my laboratory has found prominent metabolic effects of MTQAs. This does not seem surprising, given the mitochondrial targeting. However, to date, there has been relatively little interest in examining these metabolic effects as applicable for therapeutic purposes. In preliminary and published work to date, we found that MTQAs manifest dose-dependent effects to induce mitochondrial respiratory uncoupling in cultured cells. Moreover, we have preliminary evidence that they are effective in preventing obesity in mice. Somewhat surprisingly, we have data suggesting that this occurs, not only through enhanced energy expenditure, but also by inhibiting energy intake at the level of the central nervous system. This has led us to an overall hypothesis that a MTQA compound acting at the mitochondrial level can prevent obesity with minimal toxicity, and, ultimately, prove sufficient for clinical use. Briefly stated, the three specific aims of this application are: 1. Examine the effects of selected MTQA compounds for therapeutic potential based on metabolic studies in cultured cells. We propose to examine MitoQ, SKQ1, and compounds representing MitoQ and SKQ1 but with two side chain modifications for each parent compound (six compounds total). 2. Evaluate 2-3 selected compounds for their actions in a rodent model of obesity with attention to effects on energy expenditure and energy intake. 3. Select 1-2 compounds for more detailed mechanistic study directed at understanding the in vivo effects observed in aim 2. Significance and Innovation: The clinical importance of obesity among veterans is obvious. Our approach to addressing this issue is innovative. As will become clear, we will apply new and innovative methodology to look for previously unidentified mechanisms underlying the effects of MTQAs. We point out that we have no interest in the commercial development of MTQAs and, therefore, no bias towards any one particular compound. Our interest is in the scientific aspects of mild uncoupling as a possible treatment for obesity.